DNA Methylation Patterns as Noninvasive Biomarkers and Targets of Epigenetic Therapies in Colorectal Cancer

Hashimoto, Yutaka; Zumwalt, Timothy J.; Goel, Ajay

doi:10.2217/epi-2015-0013

Cited by 40 publications

(39 citation statements)

References 157 publications

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“…Alterations in DNA methylation is an early event in cancer and has been suggested for use in non-invasive diagnosis within CRC [58,59]. Overall, our analysis of methylation data indicates that hypomethylation is a prominent phenomenon within distal tumors, in contrast to hypermethylation within proximal tumors.…”

Section: Discussionmentioning

confidence: 60%

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Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

et al. 2020

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Background: Given the differences in embryonic origin, vascular and nervous supplies, microbiotic burden, and main physiological functions of left and right colons, tumor location is increasingly suggested to dictate tumor behavior affecting pathology, progression and prognosis. Right-sided colon cancers arise in the cecum, ascending colon, hepatic flexure and/or transverse colon, while left-sided colon cancers arise in the splenic flexure, descending, and/or sigmoid colon. In contrast to prior reports, we attempt to delineate programs of tumorigenesis independently for each side. Methods: Four hundred and eleven samples were extracted from The Cancer Genome Atlas-COAD cohort, based on a conservative sample inclusion criterion. Each side was independently analyzed with respect to their respective normal tissue, at the level of transcription, post-transcription, miRNA control and methylation in both a stage specific and stage-agnostic manner. Results: Our results indicate a suppression of enzymes involved in various stages of carcinogen breakdown including CYP2C8, CYP4F12, GSTA1, and UGT1A within right colon tumors. This implies its reduced capacity to detoxify carcinogens, contributing to a genotoxic tumor environment, and subsequently a more aggressive phenotype. Additionally, we highlight a crucial nexus between calcium homeostasis (sensing, mobilization and absorption) and immune/GPCR signaling within left-sided tumors, possibly contributing to its reduced proliferative and metastatic potential. Interestingly, two genes SLC6A4 and HOXB13 show opposing regulatory trends within right and left tumors. Post-transcriptional regulation mediated by both RNA-binding proteins (e.g. NKRF (in left) and MSI2 (in right)) and miRNAs (e.g. miR-29a (in left); miR-155, miR181-d, miR-576 and miR23a (in right)) appear to exhibit side-specificity in control of their target transcripts and is pronounced in right colon tumors. Additionally, methylation results depict location-specific differences, with increased hypomethylation in open seas within left tumors, and increased hypermethylation of CpG islands within right tumors. Conclusions: Differences in molecular mechanisms captured here highlight distinctions in tumorigenesis and progression between left and right colon tumors, which will serve as the basis for future studies, influencing the efficacies of existing and future diagnostic, prognostic and therapeutic interventions.

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Section: Discussionmentioning

confidence: 60%

“…8b). Previously published methylation markers including SEPT9, VIM, GATA4, INA, MAL, WNT (WNT2/ 2B/3/6/5A/7A, APC2) and CNRIP1 are hypermethylated in both RSCC and LSCC [58,59], further establishing them as side-agnostic methylation markers of CRC.…”

Section: Differences In Marker Methylation and Its Association With Gmentioning

confidence: 89%

Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

et al. 2020

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“…Therefore, it is important to recognize that colorectal neoplasms are heterogeneous in genetic and epigenetic alterations. Liquid biopsy is defined as sampling and analysis of non-solid biological tissue, primarily blood 32) . As for traditional biopsy, this technique is mainly used for diagnosis and monitoring of a disease such as cancer, with the added benefit of being largely non-invasive.…”

Section: Epigenetic Alterationsmentioning

confidence: 99%

Surgery, Perioperative Treatment and Prognostic Factors Based on Genetic and Epigenetic Alterations in Colorectal Cancer

Sugimoto

Sakamoto

2019

Juntendo Medical Journal

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In this review, we summarize the current status and provide future perspectives on surgery, perioperative treatment, and prognostic factors based on genetic and epigenetic alterations in colorectal cancer (CRC). Surgery is still the mainstay of treatment for CRC for definitive management and potential cure at an early stage, and effective palliation in advanced cases. Local control and survival have significantly improved in surgical cases because the indication for surgery and perioperative treatment has changed. Based on the results of some randomized control trials, laparoscopic surgery is now considered to be a standard treatment option for advanced colon cancer. The most recent development is robotic surgery using the da Vinci ® surgical system, which consists of a patient-site cart, a surgeon console, and a vision system. This system provides 3 dimensions high definition (3D HD) vision of a clear and magnified operative view and converts the surgeonʼs hand movements into smaller, more precise movements of tiny instruments inside the body. Thus, da Vinci ® technology allows surgeons to perform complex procedures through a few small wounds, similarly to conventional laparoscopic surgery. Genetic effects such as mutations and chromosome instability involve changes in the DNA sequence of a gene, whereas epigenetics refers to potentially heritable changes that are linked to DNA methylation or histone methylation, but do not involve changes in the DNA sequence. Genetic and epigenetic changes are linked with each other and can lead to cancer development and progression. Many recent studies have examined the relationships of these changes to diagnosis, treatment and prevention of CRC.

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“…There have also been extensive studies regarding the link between methylation and cancer. For instance, Hashimoto [15] used methylation as a biomarker for gastrointestinal tumors and Pouliot [16] used a similar approach for breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Bayesian neural networks for the optimisation of biological clocks in humans

Alfonso

González

2020

Preprint

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DNA methylation is related to aging. Some researchers, such as Horvath or Levine have managed to create epigenetic and biological clocks that predict chronological age using methylation data. These authors used Elastic Net methodology to build age predictors that had a high prediction accuracy. In this article, we propose to improve their performance by incorporating an additional step using neural networks trained with Bayesian learning. We shown that this approach outperforms the results obtained when using Horvath's method, neural networks directly, or when using other training algorithms, such as Levenberg-Marquardt's algorithm. The R-squared value obtained when using our proposed approach in empirical (out-of sample) data was 0.934, compared to 0.914 when using a different training algorithm (Levenberg Marquard), or 0.910 when applying the neural network directly (e.g. without first reducing the dimensionality of the data). The results were also tested in independent datasets that were not used during the training phase. Our method obtained better R-squared values and RMSE than Horvath's and Levine's method in 8 independent datasets. We demonstrate that building an age predictor using a Bayesian based algorithm provides accurate age predictions. This method is implemented in an R function, which is available through a package created for predicting purposes and is applicable to methylation data. This will help to elucidate the role of DNA methylation age in complex diseases or traits related to aging.

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DNA Methylation Patterns as Noninvasive Biomarkers and Targets of Epigenetic Therapies in Colorectal Cancer

Cited by 40 publications

References 157 publications

Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

Surgery, Perioperative Treatment and Prognostic Factors Based on Genetic and Epigenetic Alterations in Colorectal Cancer

Bayesian neural networks for the optimisation of biological clocks in humans

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